The field of the invention is systems and methods for preventing heart rhythm disturbances. More particularly, the invention relates to systems and methods for detecting and controlling repolarization alternans such that optional pacing of the heart can be implemented to prevent or suppress adverse cardiovascular events such as sudden cardiac death and occurrences of serious heart rhythm disturbances including ventricular fibrillation, ventricular tachyarrhythmia, and ventricular bradyarrhythmia.
Cardiovascular disease is the greatest cause of morbidity and mortality in the industrialized world. It not only strikes down a significant fraction of the population without warning, but also causes prolonged suffering and disability in an even larger number. Sudden cardiac death (“SCD”) is prevalent in the population; however, it is difficult to treat because it is difficult to predict in which individuals it will occur, and often occurs without warning in an out-of-hospital setting. It is widely acknowledged that use of implantable cardioverter defibrillators (“ICDs”) has reduced the incidence of SCD in high risk patients.
Clinical trials have suggested that the ICD is effective for secondary prevention of SCD in patients with cardiac arrest due to ventricular fibrillation (“VF”), hemodynamically compromising ventricular tachycardia (“VT”), and syncope with inducible VT. Overall, a number of studies have suggested that patients with a left ventricular ejection fraction (“EF”) less than or equal to around thirty-five percent may benefit from ICD therapy. Recently, it has been suggested that patients with coronary artery disease and left ventricular EF less than or equal to around thirty percent derive a mortality benefit from ICD therapy. As a result of such trials, the use of the ICD continues to increase worldwide.
Currently, ICDs are used as an effective therapy for the termination of heart rhythm disturbances. But, the role of ICDs is to deliver electrical impulses to terminate the arrhythmia rather than to prevent its onset. Thus, patients are being subjected to a serious arrhythmia for a period of time until therapy is delivered. Also, delivery of electrical impulses from the ICD may be painful and may damage the heart. There remains, therefore, a need to prevent arrhythmias from initiating rather than treating them with what may be much higher energy electrical pulses after the arrhythmias have been initiated.
Arrhythmias such as ventricular tachycardia and fibrillation are often caused by an electrical mechanism called reentry. FIGS. 1A-1D illustrate that reentry involves a loop-like path of electrical activation circulating through a region of heart tissue, reentering regions that had been previously activated in prior loops. In early ischemic arrhythmias, ventricular tachycardia and fibrillation have been shown to depend on reentrant excitation. Although reentrant excitation is thought to underlie a variety of benign and malignant cardiac rhythms, descriptions of the mechanisms that are involved in the development of reentry remain obscured. A major factor leading to the genesis of ventricular fibrillation during ischemia is dispersion of refractoriness. Dispersion of refractoriness is a measure of non-homogeneous recovery of excitability in a given mass of cardiac tissue. A tissue is called refractory when it cannot be re-stimulated until it has recovered. In normal myocardium the excitability is strictly proportional to the duration of repolarization. Reentry is the most likely mechanism of arrhythmia facilitated by enhanced dispersion of repolarization. The elements that are most often represented in the experimental or clinical models of arrhythmias attributed to reentry include non-uniform conduction, non-uniform excitability, and non-uniform refractoriness.
Ischemia alters refractoriness through its effects on resting potential and action potential duration. These effects are non-uniform during regional ischemia because of local variations in blood flow and diffusion of substrate and metabolites across the ischemic boundary. The resulting non-uniformity in refractoriness undoubtedly contributes to the increased vulnerability of an ischemic heart to fibrillation. An important mechanism for enhancing dispersion of refractory period is alternation of the action potential from beat to beat.
Action potential alternans involves an alternating sequence in which the shape of the action potential, which is the wave-like pattern of variation of a cell's transmembrane potential, associated with an individual cardiac cell changes on an every other beat basis. If the duration of the action potential alternates on an every other beat basis, then the duration of refractory period also alternates in duration because the refractory period is generally roughly comparable to the duration of the action potential. Thus, action potential alternans creates a situation in which a region of the myocardium has a long refractory period on an every other beat basis. On these alternate beats, a region with action potential alternans can create islands of refractory tissue that can cause fractionation of activation wavefronts. Thus, action potential alternans, which generally occurs in diseased tissue, can promote the development of reentry.
The presence of action potential alternans can be detected in an electrocardiogram (“ECG”) as an ST segment or T-wave alternans (“TWA”), which is also referred to as repolarization alternans (“RA”). In the surface electrocardiogram, repolarization alternans has been correlated with the presence of ventricular vulnerability to arrhythmias in humans. As used herein, the term “repolarization alternans” includes any change in the morphology of the ST segment or T-wave of the electrocardiogram occurring on an every other beat basis.
Computer simulations of cardiac conduction processes have predicted the relationship between the presence of electrical alternans and enhanced susceptibility to the onset of reentrant rhythm disturbances. Specifically, the simulated ECGs have shown electrical alternans in myocardial cells that have refractory periods that exceed a threshold cycle length, resulting in a corresponding subpopulation of cells that can be at most activated every second beat. This process leads to wavefront fractionation, thus being the predisposing factor to reentrant ventricular dysrhythmias.
Recent studies have demonstrated that the presence of microvolt level repolarization alternans, which is generally not visible upon visual inspection of the electrocardiogram, but detectable using advanced signal processing techniques, is associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Moreover, in ECG tracings obtained from Holter monitoring, there has been evidence that repolarization alternans persist for long periods before the onset of an unstable heart rhythm like ventricular tachycardia or ventricular fibrillation. Thus, in both computer simulations and experimental reports, repolarization alternans have been shown to increase its magnitude in the stage preceding a malignant heart rhythm like ventricular fibrillation.
Clinically, an RA test is classified as indeterminate if there is significant noise or ectopy. In early studies, indeterminate RA tests were assumed to have no predictive capability and were excluded from final analysis. However, because indeterminate RA tests account for the majority of non-negative tests, more recent studies have grouped indeterminate tests together with positive tests as abnormal. The high death rate in the indeterminate group clearly indicates that an indeterminate test has an unfavorable prognosis, but the nature of this risk is unclear. This raises the possibility that an indeterminate test may actually predict arrhythmic risk. Although this may seem counterintuitive, it is possible that patients with non-sustained alternans or frequent premature ventricular contractions (“PVCs”) are prone to ventricular arrhythmias even if the estimation of RA in these patients does not accurately classify them as being at high risk for arrhythmic events. Recent analyses of indeterminate tests have concluded that such patients are at high risk for tachyarrhythmic events, suggesting that the prognostic value of RA may be improved by reclassification of indeterminate tests.
Furthermore, there remains a need to improve the accuracy for estimation and classification of RA tests in order to reduce the false positive and false negative rates currently found. By addressing such a need, the clinical utility of RA testing for risk stratification can be improved upon.
Detection of RA further involves identifying the optimal locations in the heart to place a number of sensing leads that would maximize the probability of detecting RA. It further involves proportionately scaling the intracardiac alternans voltage and noise thresholds to account for these greater amplitudes. Failure to scale the alternans voltage and noise thresholds in this manner leads to increased sensitivity but reduced specificity for alternans detection when comparing intracardiac to body surface leads.
A reentrant waveform can be terminated by electrical pacing that is initiated within a specific period during reentrant excitation. This process gives rise to a new wave whose front collides with and annihilates the reentrant wave. A pacing stimulus occurring before complete recovery may induce graded responses and hence prolong the action potential and refractoriness. When the leading edge of the reentrant wavefront revisits this area it cannot reenter. This circumstance results in bi-directional block and the termination of reentry. Thus, the use of pacing as a method to terminate ventricular arrhythmias may result in the termination of reentry and VF; changes in the shape, or position of the shape, of the center of the activity and induction of different reentrant waveforms or a focal pattern of repetitive activation; changes in the “exit” pathway, or in the direction, of the activity; or resetting of the activity and persistence of the same reentry.
In light of the foregoing considerations, there remains a need to prevent arrhythmias from initiating rather than treating the arrhythmias with what may be much higher energy electrical pulses after the arrhythmias have been initiated. Thus, it would be highly desirable to be able to prevent arrhythmias from starting rather than terminating them after their initiation by administration of an electrical shock. There also remains a need to more accurately estimate the initiation of cardiac arrhythmias, so that they can be prevented before initiation occurs.